The ability to identify and characterize mechanisms affecting longitudinal growth and articular cartilage extracellular architecture carries with it the potential for fashioning novel techniques of early diagnosis and intervention. The focus of the proposed studies, cartilage oligomeric matrix protein (COMP), is a previously little-studied noncollagenous protein that appears to have a profound influence on musculoskeletal growth and function, as illustrated by the recent identification of mutations in COMP gene in two types of inherited chondrodysplasias and osteoarthrotic phenotypes, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), conditions characterized by disrupted longitudinal growth and early-onset arthritis. The hypothesis of this proposal is that mutations in the calcium-binding molecular domains of COMP alter its three-dimensional structure and function in such a way as to impede appendicular longitudinal growth and compromise cartilaginous extracellular matrix integrity. Studies will be undertaken to (1) examine how a point mutation in the calcium-binding domains of COMP disrupts known COMP functions; and (2) determine, utilizing a transgenic model, how this process results in PSACH and MED. Identifying the functions, synthesis, interactions, tissue distribution and expression of COMP is critical to understanding its influence on growth during endochondral ossification and articular cartilage structure and function.